The effect(s) of nutrition on viral disease has not been well studied. The currently accepted model for the influence of nutrition on viral pathogenesis invokes host factors, such as a decreased immune response, which are responsible for the increased susceptibility of malnourished individuals to disease. However, little attention has been focused on the pathogen itself, which is replicating in a nutritionally deficient host. Previous work in our laboratory demonstrated that increased oxidative stress in a coxsackievirus-infected mouse, due to a dietary deficiency in either selenium or vitamin E, led to mutations in a normally avirulent strain of coxsackievirus, causing it to become virulent. Once the avirulent virus had mutated in the nutritionally deficient host, it could now cause disease even in hosts with normal nutriture. Thus, we showed for the first time that the nutritional status of the host can have a profound effect on the genome of a virus, changing an avirulent virus to a virulent one. For this application, we propose to study the outbreak of optic and/or peripheral neuropathy which occurred in Cuba in the early 1990's. The disease was associated with major changes in the Cuban diet resulting in decreases in vitamins A, B complex and E and selenium, with smoking as a co- factor. In addition to the nutritional deficiency, a coxsackie- like virus was isolated from the cerebrospinal fluid of 105 out of 125 patients tested, suggesting a co-factor role for this virus in the etiology of the disease. Again, the virus was altered compared to the prototype coxsackievirus from which it may have arisen, and the clinical syndrome differed from those previously associated with coxsackievirus infections of the central nervous system. We have sequenced one variant isolate from a patient diagnosed with nutritionally-induced optic neuropathy and found that although it is closely related to coxsackievirus A9, mutations in various regions of the virus suggest that alterations in its pathogenic expression is possible. We propose to use the Cuba epidemic as a model for a viral disease induced by a nutritional deficiency. We propose to use sequence analysis to study the evolution of the variant virus during the epidemic of optic neuropathy in order to understand the role of nutrition in the emergence of this disease. In addition, we will utilize cell culture techniques to further dissect the mechanism by which the viral mutations occur. Taken as a whole, we believe these studies will provide important new information on the critical role nutrition plays in the development of new viral variants with unpredictable pathogenic properties, a long neglected area of study.